Studies of cocaine abusers often show evidence of decreased brain function as well as abnormalities in brain structure. Attributing these deficits directly to the chronic abuse of cocaine itself can be quite challenging in this population. Cocaine abusers often use multiple legal and illegal drugs over varying durations, have co-morbid psychiatric conditions, and experience different life experiences than their non-drug using controls. In addition, many of these differences may have pre-dated any drug use. One approach to this challenge is the use of animal models in which factors can be varied systematically and the role of each factor determined with greater confidence. During the past funding period we have employed a non-human primate model of cocaine self-administration to characterize the changes in the network of changes in cerebral metabolism that accompanies chronic cocaine exposure and the modifications of these changes with abstinence. In the present application we propose to continue use of this model to answer the following questions. First, do the neuroadaptations in brain structure and function in response to cocaine result in residual changes in basal brain activity? Second, how do these neuroadaptations influence the functional response to drug-associated cues and how does this response compare to the response to cocaine itself? Third, what is the neurobiological impact of a pharmacological intervention with replacement therapy in animals chronically exposed to cocaine? These studies will combine careful behavioral analysis with detailed imaging investigations to answer these questions. Despite significant treatment and prevention efforts, cocaine abuse remains an ongoing public health problem. Completion of the studies proposed in this application will provide the data essential for more effective evaluations of treatment strategies for cocaine abuse and dependence. In addition, these studies will provide new information about the interaction of potential pharmacological therapies with the brain changes associated with chronic cocaine exposure, as well as the persistence of these changes over the course of abstinence from drug use.